MiR-100 is a predictor of endocrine responsiveness and prognosis in patients with operable luminal breast cancer.

PURPOSE: Overexpression of miR-100 in stem cells derived from basal-like breast cancers causes loss of stemness, induction of luminal breast cancer markers and response to endocrine therapy. We, therefore, explored miR-100 as a novel biomarker in patients with luminal breast cancer. METHODS: miR-100 expression was studied in 90 patients with oestrogen-receptor-positive/human-epidermal growth factor receptor 2-negative breast cancer enrolled in a prospective study of endocrine therapy given either preoperatively, or for the treatment of de novo metastatic disease. Response was defined as a Ki67 ≤2.7% after 21±3 days of treatment. The prognostic role of miR-100 expression was evaluated in the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and The Cancer Genome Atlas (TCGA) breast cancer datasets. Additionally, we explored the correlation between miR-100 and the expression its targets reported as being associated with endocrine resistance. Finally, we evaluated whether a signature based on miR-100 and its target genes could predict the luminal A molecular subtype. RESULTS: Baseline miR-100 was significantly anticorrelated with baseline and post-treatment Ki67 (p<0.001 and 0.004, respectively), and independently associated with response to treatment (OR 3.329, p=0.047). In the METABRIC dataset, high expression of miR-100 identified women with luminal A tumours treated with adjuvant endocrine therapy with improved overall survival (HR 0.55, p<0.001). miR-100 was negatively correlated with PLK1, FOXA1, mTOR and IGF1R expression, potentially explaining its prognostic effect. Finally, a miR-100-based signature developed in patients enrolled in the prospective study outperformed Ki67 alone in predicting the luminal A phenotype. CONCLUSIONS: Our findings suggest that miR-100 should be further explored as a biomarker in patients with luminal breast cancer.

Reoperation rate after breast conserving surgery as quality indicator in breast cancer treatment: A reappraisal.

AIM: To analyse the role of repeated breast surgery (RBS) after breast conserving surgery (BCS) as a quality indicator in a consecutive series of breast cancer patients. METHODS: Data from 1233 breast cancer patients submitted to BCS from 2015 to 2019 were reviewed. The influence of several variables on RBS rate (182/1232; 14.8%) was examined. Univariate and multivariate analyses were conducted to look for significant associations with the risk of RBS. RESULTS: Surgical workload, BCS rate and clinicopathological variables were consistent over the study period, while RBS rate decreased after the introduction of shaving of cavity margins (from 17.9% to 9.5%). Tumor persistence at RBS was higher for mastectomy vs. re-excision (87.3% vs. 37.8%; p = 0.05), inconclusive vs. positive diagnostic biopsy (48.2% vs. 69.4%; p = 0.003), ductal carcinoma in situ vs. invasive carcinoma (69.0% vs. 51.3%; p = 0.046) and lower after neoadjuvant therapy (14.3% vs. 57.8%; p = 0.044). Several clinicopathological variables were associated with the risk of RBS, but only multifocality [Odds Ratio (OR): 1.8; p = 0.009], microcalcifications (OR: 2.0, p = 0.000), neoadjuvant therapy (OR: 0.4; p = 0.014), pathological intraoperative assessment (OR: 0.6; p = 0.010) and shaving of cavity margins (OR: 0.3; p = 0.000) retained independent value at multivariate analysis. CONCLUSIONS: RBS rate can be reduced by shaving of cavity margins. Current standards for RBS should not be made more stringent due to the existence of non-actionable risk factors. The value of RBS as a quality indicator should be scrutinzed.

Primary tumor location predicts the site of local relapse after nipple-areola complex (NAC) sparing mastectomy.

PURPOSE: To assess the oncological safety of nipple-areola complex (NAC) sparing mastectomy in breast cancer patients. METHODS: From 2010 to 2015, 518 breast cancer patients were submitted to NAC sparing mastectomy. Breast MRI and intraoperative assessment of the subareolar (SD) and proximal (ND) nipple ducts were performed to predict NAC involvement. Significant associations between pre- and postoperative variables with SD/ND involvement and with the risk of local recurrence were retrospectively investigated. RESULTS: SD/ND were involved in 26.1% of the cases. Final pathology of SD/ND was predicted by tumor-NAC distance at MRI and intraoperative pathology with 75 and 93% accuracy, respectively. NAC involvement was more frequent in case of positive ND than positive SD (68.3 vs. 38.3%; p = 0.003). Fourteen (2.7%) local relapses developed over a mean follow-up of 33 months. Ki-67 ≥25% (p = 0.002) and high tumor grade (p = 0.027) correlated with local recurrence. Most relapses developed in the subcutaneous tissue of the quadrant where the primary tumor was located (12/14; 85.7%). No local relapses occurred in patients who received post-mastectomy radiotherapy as compared to patients who did not, although they had a higher rate of positive surgical margins (40.5 vs. 16.2%; p = 0.000). CONCLUSIONS: NAC involvement can be predicted by MRI and intraoperative pathology of ND/SD. Local recurrences after NAC sparing mastectomy almost invariably develop in the same quadrant where the primary tumor was located and in highly proliferative tumors.

Omission of axillary dissection after a positive sentinel lymph-node: Implications in the multidisciplinary treatment of operable breast cancer.

Omission of axillary dissection in women with breast cancer and one or two positive sentinel-node biopsy is a major advancement in the management of this disease. Supported by a sound rationale and confirmed by prospective, randomized trials, omission of axillary dissection is now recommended in women who have undergone breast conserving surgery and who are candidate to adjuvant radiotherapy. Because breast cancer is best managed in the context of a multidisciplinary team, this surgical shift in the paradigm is expected to have implications that extend also to the other specialties involved in the team. In fact, the full evaluation of the axillary tumor burden has been historically considered an essential part of tumor staging and the absolute number of involved node critical information to tailor post-surgical treatments. Lack of this information in a patient with axillary involvement documented by a positive sentinel lymph-node biopsy may represent a challenge when deciding on further, post-surgical treatments. This review will address the critical aspects and the potential implications of omission of axillary dissection in the context of the multidisciplinary breast team.

Ovarian cancer in BRCA1 and BRCA2 gene mutation carriers: analysis of prognostic factors and survival.

OBJECTIVES: To compare clinical-pathological characteristics and outcome between sporadic ovarian cancer and ovarian cancer in patents with hereditary breast and ovarian cancer syndrome (HBOC). METHODS: Twenty-four patients with ovarian cancer treated between 2000 and 2009 who tested positive for BRCA1/2 mutation (BRCA+) and a control group of 64 age-matched patients with no family history of breast/ovarian cancer (controls) were enrolled. Clinical-pathological characteristics, surgical outcome, overall (OS), and progression-free survival (PFS) were compared between the two groups. RESULTS: The high-grade serous histotype was more represented in BRCA+ than in controls (70.8% versus 53.1%) (p > 0.05). BRCA+ cancers were more frequently diagnosed at stage II than controls (20.83% versus 4.69%) (p = 0.024). Radical primary surgery was performed in 70% of women in both groups, with no difference in debulking results. In patients undergoing surgery after neoadjuvant chemotherapy, in all BRCA+ patients, optimal cytoreduction was achieved (versus 70% of the controls). PFS was significantly longer for BRCA+ patients compared to controls (60 months versus 22 months; p = 0.039). No significant difference was observed in OS between BRCA+ patients and controls. CONCLUSIONS: At a median follow-up time of 46 months, BRCA+ patients have a better prognosis than controls in terms of PFS. Higher chemosensitivity of BRCA+ tumours was observed.

MRI and intraoperative pathology to predict nipple-areola complex (NAC) involvement in patients undergoing NAC-sparing mastectomy.

BACKGROUND: Nipple-areola sparing mastectomy (NSM) with immediate implant reconstruction is an option for patients with non-locally advanced breast cancer. The prediction of occult tumour involvement of the nipple-areola complex (NAC) may help select candidates to NSM. PATIENTS AND METHODS: We prospectively recorded clinical and pathological data, magnetic resonance imaging (MRI) results and intraoperative pathological assessments of the subareolar (SD) and proximal nipple ducts (ND) of 112 consecutive breast cancer patients scheduled for NSM. All parameters were correlated with final pathological NAC assessment by univariate and multivariate analysis. RESULTS: Thirty-one patients (27.7%) had tumour involvement of the NAC. At univariate analysis, age (p=0.001), post-menopausal status (0.003), tumour central location (p=0.03), tumour-NAC distance measured by MRI (p=0.000) and intraoperative pathologic assessment (SD+ND) (p=0.000) were significantly correlated with NAC involvement. At multivariate analysis, only MRI tumour-NAC distance (p=0.008) and menopausal status (p=0.039) among all preoperative variables retained statistical significance. The sensitivity and specificity of MRI tumour-NAC distance were 32.2% and 88.6% and those of intraoperative pathologic assessment were 46.7% and 100%, respectively. Sensitivity, specificity and accuracy of the double assessment (MRI plus intraoperative pathology) were 50.0%, 96.2% and 84.1%, respectively. CONCLUSION: Intraoperative pathologic assessment and tumour-NAC distance measured by MRI are the most important predictors of occult NAC involvement in breast cancer patients. A negative pathological assessment and a tumour-NAC distance ⩾ 5 mm allow optimal discrimination between NAC positive and NAC negative cases and may serve as a guide for the optimal planning of oncological and reconstructive surgery.

Body mass index (BMI) and breast cancer: impact on tumor histopathologic features, cancer subtypes and recurrence rate in pre and postmenopausal women.

The study aims to analyze the association between body mass index (BMI) at time of diagnosis, breast cancer histopathologic features (tumor size, nuclear grade, estrogen and progesterone receptor (ER and PgR) and HER-2/neu expression, histological subtypes, Ki-67 index, lymphatic/vascular invasion, axillary nodes involvement) and incidence of different subtypes defined using hormone receptors and HER2/neu expression, according to menopausal status; to evaluate the impact of BMI on disease free survival (DFS) at multivariate analysis. A total of 2148 patients (592 premenopausal, 1556 postmenopausal) were classified into subgroups according to BMI distribution. High BMI was significantly associated with larger size tumor both in pre (p = 0.01) and postmenopausal women (p = 0.00). Obese premenopausal women showed worse histopathologic features (more metastatic axillary lymphnodes, p = 0.017 and presence of vascular invasion, p = 0.006) compared to under/normal weight group. Postmenopausal patients with BMI > 25 developed more frequently ER/PgR positive cancers (87% versus 75%, p 0.017), while no association was found in premenopausal women. We could not found any statistically significant correlation between breast cancer subtypes (luminal A, B, HER-2 and basal-like) and BMI both in pre and postmenopause. Higher BMI was significantly associated with a shorter DR-FS in postmenopausal women but the independent prognostic role of obesity was not confirmed in our analysis.

Effects of surgical and adjuvant therapies for breast cancer on sexuality, cognitive functions, and body weight.

INTRODUCTION: Breast cancer and its treatment negatively affect the important aspects of a woman's life such as sexual health, cognitive functions, body image, and weight. Abrupt estrogen deficiency following chemotherapy and/or hormonal therapy plays an important role in worsening of sexuality. AIM: To evaluate the impact of breast cancer treatment on sexual functioning, cognitive function, and body weight in premenopausal women. METHODS: Thirty-five women with a premenopausal diagnosis of breast cancer who are candidate to adjuvant treatment completed validated questionnaires on menopausal symptoms, sexuality, partner relationship, depression, body image, and cognitive functions after surgery (T0), then after chemotherapy or at least 6 months of endocrine therapy (T1), and after 1 year (T2). In addition, gynecological and dietological examinations were performed. MAIN OUTCOME MEASURE: The following validated questionnaires were used: Greene Climacteric Scale, Beck Depression Inventory, Body Attitude Test, McCoy revised Italian version McCoy Female Sexuality Questionnaire, Cues for Sexual Desire Scale, Dyadic Adjustment Scale, Numeric Matrix Test and Rey auditory-verbal learning test, to measure cognitive functions, a recall 24 H questionnaire to evaluate food intake, Minnesota Leisure Time Physical Activity questionnaire and Eating Attitude Test-40, while anthropometric and plicometry data were assessed by a dietitian. RESULTS: Low levels of sexual functioning were registered at baseline; a further decrease in sexual activity, quality of the partnered relationship, desire, and arousability was demonstrated at T1 and T2. We found a significant increase in hot flushes and anxiety. Nonsignificant deterioration of body image was demonstrated. Although women reported losing memory and concentration, "chemobrain" effect was not demonstrated as cognitive tests improved after 6 months, probably because of "learning effect." Women who had undergone chemotherapy gained weight and fat disposition was typically android. CONCLUSIONS: Young women undergoing adjuvant breast cancer therapy experience a heavy impairment in important quality of life domains as sexuality and targeted support interventions are needed.

Low-dose vaginal estrogens or vaginal moisturizer in breast cancer survivors with urogenital atrophy: a preliminary study.

The study aim is to evaluate the efficacy and safety of two low-dose vaginal estrogen treatments (ETs) and of a non-hormonal vaginal moisturizer in postmenopausal breast cancer survivors with urogenital atrophy. Eighteen patients receiving estriol cream 0.25 mg (n = 10) or estradiol tablets 12.5 microg (n = 8) twice/week for 12 weeks were evaluated and compared with eight patients treated with polycarbophil-based moisturizer 2.5 g twice/week. Severity of vaginal atrophy was assessed using subjective [Vaginal Symptoms Score (VSS), Profile of Female Sexual Function (PFSF)] and objective [Vaginal Health Index (VHI), Karyopycnotic Index (KI)] evaluations, while safety by measuring endometrial thickness and serum sex hormones levels. After 4 weeks, VSS and VHI were significantly improved by both vaginal ETs, with further improvement after 12 weeks. PFSF improved significantly only in estriol group (p = 0.02). Safety measurements did not significantly change. Vaginal moisturizer improved VSS at week 4 (p = 0.01), but score returned to pre-treatment values at week 12; no significant modification of VHI, KI, PFSF was recorded. Both low-dose vaginal ET are effective for relieving urogenital atrophy, while non-hormonal moisturizer only provides transient benefit. The increase of serum estrogens levels during treatment with vaginal estrogen at these dosages is minimal.

Mirtazapine for the treatment of hot flushes in breast cancer survivors: a prospective pilot trial.

The purposes of the study are to evaluate the efficacy and safety of mirtazapine 30 mg/daily for 12 weeks to reduce hot flushes (HF) in women with previous breast cancer and to assess the influence of the same treatment on sleep quality and other menopausal symptoms. A prospective pilot trial was conducted in 40 breast cancer patients with at least seven HF per day. A HF diary was completed daily; sleep quality and other menopausal symptoms were assessed with the Pittsburgh Sleep Quality Index (PSQI), the Menopause Rating Scale (MRS) and the SF-36 Health Survey. Treatment was never started by 13 out of 40 patients (32.5%) and was interrupted by 7 out of 27 patients (25%) due to of the occurrence of side effects (mostly somnolence). In the remaining 20 patients who completed the three months treatment period, there was a 55.6% (p < 0.05) reduction in HF frequency and 61.9% (p < 0.05) reduction in HF score as compared to baseline. A significant reduction in the MRS score (32.8%; p < 0.05) was observed. Mirtazapine appears to be effective in reducing HF in breast cancer survivors. The more frequent side effect was somnolence. A sizeable compiliance problem has been observed due to the reluctance to take antidepressant drugs and to side effects.

Personal use of hormone therapy by postmenopausal women doctors and male doctors' wives in Italy after the publication of WHI trial.

OBJECTIVE: To describe the prevalence of hormone replacement therapy (HT) use by postmenopausal women doctors and doctors' wives in Italy and to explore the relationship between their personal characteristics and HT use. DESIGN: A total of 500 women doctors and 500 men doctors answering on behalf of their female partners were interviewed by a specialised company in the first months of 2003. Questions were meant to explore medical, behavioural and professional characteristics, personal use of HT, reasons for or against HT use and side effects of HT. The distribution of doctors' specialisation (general practitioners (GPs), gynaecologists, medical oncologists) in the sample interviewed was the same as that of the Italian medical community. RESULTS: Overall, 37% of women doctors and 39% of doctors' wives had ever used HT after menopause, of which 64 and 58%, respectively, were current users. The median duration of HT in the past users was 2.7 years for women doctors and 3.7 for doctors' wives. There were wide differences of HT use according to the type of specialisation: gynaecologists were more willing to use HT (56-59%) than GPs (30-31%) or medical oncologists (16-30%). Vasomotor symptoms (68-69%), followed by the prevention of osteoporosis (28-39%), were the main reasons for commencing HT. The main reasons not to take or to stop HT were the absence or resolution of menopausal symptoms. Only 8% of women doctors and 4% doctors' wives stopped HT after the publication of the WHI data. CONCLUSIONS: In Italy, women doctors/doctors' wives personally use HT much more than postmenopausal general population.